The present invention, in some embodiments thereof, relates to novel NKp46 antibodies and, more particularly, but not exclusively, to the use of same for preventing and/or treating malignant and autoimmune diseases.
Natural killer (NK) cells are innate effector lymphocytes, first identified in 1975 for their ability kill tumor cells without prior stimulation. To date, NK cells have emerged as one of the most crucial first responders to tumor transformation and viral, bacterial, or fungal infections. They are also involved in autoimmune diseases such as type I and type II diabetes. NK cells have cytotoxic activity and can secrete cytokines; hence they are part of the newly characterized family of Innate Lymphoid Cells (ILCs). They are classified as Group 1 ILCs, mainly due to their production of type 1 cytokines (IFNγ and TNFα). NK cells have the distinct ability to recognize many diverse targets due to their numerous germ-line encoded activating and inhibitory receptors. A balance of signals received by these receptors ultimately determines whether the NK cells act against a given target cell, or remain neutral.
Three activating receptors found on NK cells, NKp30, NKp44, and NKp46, are collectively known as Natural Cytotoxicity Receptors (NCRs). These receptors are crucial in NK cells antitumor and antiviral defenses. NKp46 has been established as a critical activating receptor since it is expressed almost exclusively by NK cells and is the only NCR with a mouse orthologue. Its ligand repertoire ranges from viral ligands, such as, hemagglutinin (HA) and hemagglutinin-neruamindase (HN) of influenza virus, Sendai virus, Newcastle disease virus, and poxvirus, to unknown ligands found on bacteria, such as Fusobacterium nucleatum, tumors, adipose cells, and human pancreatic beta cells. The identification of the unknown ligands, in particularly the tumor ligands of NKp46, has been intensely investigated for over a decade.
NKp46 is part of the IgG superfamily, and consists of two C2-type Ig-like domains: D1 is the membrane distal domain and D2 is the membrane proximal domain. Interestingly, the D1 domain was shown to not be involved in NKp46 ligand recognition, and binding was solely mediated by its D2 domain (which also contains the stalk and hinge regions). Different features within the D2 domain determine binding to various ligands. For example, there are three glycosylation sites, Asn216, Thr125 and Thr225 which are commonly involved in the binding to different ligands. HA recognition by NKp46 was shown to be sialic acid dependent, primarily mediated by the residue Thr225, which is also involved in the recognition of some but not all tumors. Asn216 and Thr125 both participate in the recognition of human beta cells, and the unknown ligand on F. nucleatum, does not require sialyation. This unique feature of NKp46, where it binds different ligands using diverse features and binding sites, has hindered research involving the function of NKp46. Furthermore, the biological relevance of the D1 domain of NKp46 remains elusive.